CEREBRAL MITOCHONDRIAL METABOLISM IN NEURODEGENERATION

神经退行性变中的大脑线粒体代谢

• 批准号: 6344240
• 负责人: WILLIAM J POWERS
• 金额: $ 34.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344240
• 关键词: Huntington's disease; Parkinson's disease; adult human (21+); brain metabolism; caudate nucleus; cerebral degeneration; diagnosis design /evaluation; electron transport; glucose metabolism; human subject; magnetic resonance imaging; mitochondria; nervous system disorder diagnosis; neuropsychological tests; patient oriented research; platelets; positron emission tomography; putamen; substantia nigra

DESCRIPTION (Adapted from the abstract provided by the applicant): Several lines of evidence suggest that Huntington's disease (HD) and Parkinson's disease (PD) have defects in mitochondrial function that impair oxidative phosphorylation and play a key role in the mechanism of neuronal death. To date, however, there have been no direct measurements of cerebral oxygen to glucose metabolic ratios to demonstrate an in vivo defect in cerebral mitochondrial metabolism in these diseases. We will use positron emission tomography (PET) to measure in vivo regional cerebral oxygen metabolism (CMR02) and cerebral glucose metabolism (CMRglc) to test two primary hypotheses: 1) Patients with HD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 gene-positive pre-symptomatic patients with HD, 15 gene-positive patients with HD and definite motor signs and 30 age/gender-matched normal controls. 2) Patients with PD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 never-medicated, early PD patients and 15 age/gender-matched normal controls. In the same subjects, we also will test two secondary hypotheses: 3) Regions vulnerable to pathologic insult have larger magnitude or selective defects in cerebral mitochodrial metabolism - caudate and putamen in HD and substantia nigra and putamen in PD. 4) In PD and HD, the degree of dysfunction in platelet electron transport complex function measured in vitro correlates with the degree of abnormal cerebral mitochondrial metabolism measured in vivo. At this time it is not clear how the abnormalities in electron transport chain activity measured in vitro in these two diseases correspond to cerebral mitochondrial metabolism in vivo. Direct in vivo regional PET measurements of CMR02 and CMRglc will allow us to demonstrate the extent and magnitude of mitochondrial dysfunction in vivo. Establishing the existence of cerebral mitochondrial dysfunction early in the course of these diseases will not only provide insights into the pathogenesis, but it will provide a measurable biological abnormality that can be monitored to determine the effect of treatments aimed at slowing or halting the progression of neuronal loss. The opportunity to determine the relation between platelet mitochondrial function and cerebral mitochondrial metabolism in patients with PD and HD is uniquely important. If such a relationship can be established in untreated patients in this study, then we would pursue further studies to determine the effects on cerebral mitochondrial metabolism of agents that alter platelet mitochondrial function. If such studies yield consistent results, they will establish the basis for the utilization of platelet rnitochondrial function assays to monitor cerebral mitochondrial metabolism.

描述（改编自申请人提供的摘要）：若干 一系列证据表明亨廷顿病 (HD) 和帕金森病 疾病 (PD) 线粒体功能缺陷会损害氧化 磷酸化在神经元死亡机制中发挥关键作用。到 然而，到目前为止，还没有直接测量脑氧含量来 葡萄糖代谢比率以证明大脑的体内缺陷 这些疾病中的线粒体代谢。我们将使用正电子发射 断层扫描（PET）测量体内局部脑氧代谢（CMR02） 和脑葡萄糖代谢 (CMRglc) 来检验两个主要假设：1) HD 患者脑线粒体普遍存在缺陷 代谢。为了验证这一假设，我们将测量全脑 CMR02/CMRgIc 在 15 名基因阳性的 HD 症状前患者中，15 名基因阳性患者 具有 HD 和明确的运动体征以及 30 个年龄/性别匹配的正常对照。 2） PD患者存在脑线粒体普遍缺陷 代谢。为了验证这一假设，我们将测量全脑 CMR02/CMRgIc 15 名从未接受过药物治疗的早期 PD 患者和 15 名年龄/性别匹配的正常人 控制。在同一主题中，我们还将检验两个次要假设：3) 易受病理损伤的区域具有较大的幅度或选择性 脑线粒体代谢缺陷 - HD 和壳核中的尾状核和壳核 PD 中的黑质和壳核。 4) PD和HD中功能障碍的程度 体外测量的血小板电子传递复合物功能相关性 用体内测定的脑线粒体代谢异常程度。 目前还不清楚电子传递链的异常是如何发生的 在这两种疾病中体外测量的活动对应于脑 体内线粒体代谢。直接体内局部 PET 测量 CMR02 和 CMRglc 将使我们能够展示 体内线粒体功能障碍。证实大脑的存在 这些疾病早期的线粒体功能障碍不仅会 提供对发病机制的见解，但它将提供可测量的 可以监测以确定影响的生物学异常 旨在减缓或阻止神经元损失进展的治疗。这 有机会确定血小板线粒体功能之间的关系 PD 和 HD 患者的脑线粒体代谢是独特的 重要的。如果这种关系可以在未经治疗的患者中建立 这项研究，然后我们将进行进一步的研究以确定对 改变血小板线粒体的药物的脑线粒体代谢 功能。如果此类研究得出一致的结果，他们将建立 利用血小板线粒体功能测定进行监测的基础 脑线粒体代谢。